Student Researcher and Supervisor This dissertation is taken by Fatemeh Bamdad, Master of Science in Biomedical Engineering at University of Surrey,UK,

with background of Biomedical engineering at Islamic Azad University of Tehran, Iran, under the supervision of Dr Daniel Absolo,Senior Lecturer in Biomedical Engineering, University of Surrey,UK. Project Title Non-linear analysis of the electroencephalogram in epileptic patients. Project Objectives The aim of this project is analysing the electroencephalogram (EEG) in epileptic patients with non-linear dynamics techniques, estimating the effectiveness of these methods in detection and possible prediction of epileptic seizures. We are going to focus on Approximate Entropy method in order to analysis the signal. Background to the Project Epilepsy is described as the spontaneous and unpredictable attack of seizures. This seizure depicts the extreme and hyper-synchronized activity of neurons in the brain. Epilepsy is one of the common neurodegenerative disorders which around 1% of the worlds population suffer from this disease [1]. The seizures may occur in almost every cortical region. These seizures never make the patient aware of occurrences. In some cases during a surgical process the region of the brain that probably generates seizures can be removed. These kinds of surgeries are both risky and expensive and of course have their own side effects. In some other patients a long-term treatment with antiepileptic drugs is needed. Nowadays, the neurologists are trying to find a way to predict the occurrence of epileptic seizures for the reason that therapeutic possibilities would change dramatically by means of anticipation [2]. For several decades, electroencephalography has been used to pave the way for investigation of brain electrical activity in different physiological and pathological states [3]. The electroencephalogram (EEG) is a complex signal with statistical properties including time and space. This signal has various characteristics, such as the existence of limit cycles (alpha activity, ictal activity), index of the percentage of burst supersession (which is related to depth of anaesthesia and percentage of consciousness), jump phenomena (hysteresis), amplitude dependent frequency behaviour (the smaller the amplitude the higher the EEG frequency) and frequency harmonics, are can be listed of typical properties of nonlinear systems. Observation of
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different kinds of nonlinearities in the EEG recorded from epileptogenic brain can clearly prove the concept that epileptogenic brain is a nonlinear system [4]. By introducing the nonlinear techniques, researchers have accentuated the importance of this issue that the EEG of the epileptic brain is a nonlinear signal with both

deterministic and perhaps chaotic properties [4]. On an electroencephalogram (EEG), the period during which a seizure happens is referred to as the ictal period; the period between seizures is, thus, the interictal period. One of the sign of epilepsy is the presence of spikes in the EEG during this interictal period [5]. During the generation of a seizure, harmonized epileptic brain activity begins to be observed in a small region of brain and this activity widens to other brain regions. This process gradually changes the EEG wave. By analysing this wave we aim to detect and possibly predict seizures. This would improve the quality of life for epileptic patients who cannot be treated effectively. The identification of an epileptic seizure can also be achieved by the observation of the increase in synchronized activity and increased signal complexity [6]. Although the traditional linear analysis, such as Fourier transforms and power spectrum analysis has been used for seizure prediction, it has some limitations. Consequently non-linear methods have superseded the old fashion linear analysis. Several non-linear methods have been known in recent several decades. The chaos theory expresses the non-linear behaviour of a dynamical system which becomes possible to study self-organization and pattern formation in the complex neuronal networks of the brain [7]. The most common methods of chaos analysis include the correlation dimension [8], Lyapunov exponents [9] and reversion curves and related analysis [10]. Although these standards express the general non-linear dynamics of a system, they cannot illustrate the slight differences between dynamical states, especially when the data is short and noisy. In particular, we have to bear in mind that EEG signals are always contaminated with noise [11]. Besides, another disadvantage of using the chaos analysis is that an inappropriate selection of the data may affect the results [12]. Also, to obtain a reliable response with these methods, we need long and stationary data while the EEG signals can only be considered stationary for short periods [12]. Recently, in some cases researchers have used both linear and non-linear methods at the same time to diagnose the epilepsy, but this combination method is complex and expensive for clinical usage
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[13]. The gloss of all of the results via any kinds of these methods in terms of functional sources and functional networks illustrates three basic patterns of brain dynamics [7] Other non-linear techniques without the drawbacks of the chaos theory techniques are needed to analyse the EEG: (i) Normal, resting state in healthy volunteer , steady dynamics during a no-task; this situation is described by a high dimensional complexity and a relatively low and fluctuating level of synchronization of the neuronal networks; (ii) Hyper synchronous, highly non-linear dynamics of epileptic seizures; (iii) Dynamics of degenerative encephalopathy with an abnormally low level of between area synchronization [7]. Literature review of the subject Studies conducted by different researchers illustrate how many different methods were applied to diagnosis and/or prediction of seizure in epileptic patients. Some of the most important of these methods are listed below. As far as history is concerned, the use of nonlinear time series analysis emerges in the early 1980s. They used largest Lyapunov exponent to illustrate changes in brain dynamics. Researchers in their first studies have applied correlation dimension as a measure for neuronal complexity in the EEG or the correlation density to predict the seizure a shortly before the occurrence. These studies traced by other methods including dynamical similarity and dynamical entrainment. Recently, an effort on prediction of seizure by means of certain signal patterns (bursts) and changes in signal energy has been accomplished [14]. In 1998 Osorio et al. have introduced a method to access automated seizure detection. Their method based on frequency analysis. They combined linear and non-linear filtering techniques as well as using discrete wavelet transform. In order to minimize the noise, they first analyzed intracranial signals and then developed for scalp recordings. Their incipient results revealed that this new method is the fastest and

most reliable to date. Their experiment was on 5 patients, and totally 20 seizure segments and 7 interictal segment recorded. By means of this method, the seizure detection, on average, was 16 seconds before occurrence of seizure. No seizures losing and no false detections were reported [15]. At the same time, 1998, Lehnertz and Elger used effective correlation dimension method [4]. First of all they focused on the index of Lyapunov and found the positive Lyapunov exponent in EEG signals of epileptic patients. In the second step, they
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studied intracranial and scalp EEG recordings in patients whom afoul of intractable seizures in their mesial temporal origin. They used the non-linear extension of an autoregressive (AR) model. This model is using to illustrate the existence of selfsustained nonlinear oscillations during the seizure (ictal EEG). In this step they clarified that nonlinearities in interictal EEG generated by the epileptogenic focus [4]. In 2001, Le Van Quyen et al. analysed 23 patients with temporal-lobe epilepsy [16]. They used the similarity index method and predicted the seizure about 7 minutes before occurrence. This method measures the similarity between pairs of EEG

windows and calculates the cross correlation integral between the two dynamics. The similarity index is a number below or equal to 1. Depends on the stationary of the EEG signal or changes in the dynamical state the yield respectively will be equals to below 1 or 1 [16]. American Clinical Neurophysiology Society in 2001 published an article in which Jerger et al. compared seven different methods of early seizure detection [17]. They worked on both linear and non-linear methods including analysis of power spectra, cross-correlation, principal components, phase, wavelets, correlation integral and mutual prediction. They concluded that all seven methods were successful. They did not show clear main differences between linear and non-linear methods, but they signified that the analysis of phase performed slightly better than the other methods. The phase analysing is more sensitive in detecting weakly coupled nonlinear systems [17]. In the late 2002, Mormann et al. used another method which was synchronization decrease [14]. They recorded the signals from 18 epilepsy patients and used moving window techniques in order to analysing their datasets. By analysing the synchronization between EEG signals from different regions of the brain they revealed that a large majority of analyzed seizures are recognizable by a decrease in synchronization between specified recording sites [14]. Thomas Maiwald et al. published an article in 2004 in which they compared three different non-linear methods to predict the epileptic seizure [3]. These three methods were Dynamical similarity index, Effective correlation dimension and Increments of accumulated energy. They stated that by means of three main characteristics we can determine the best way for prediction of seizure including maximum false prediction rate (FPR max), the seizure prediction horizon (SPH) and seizure occurrence period (SOP). By calculating each three characteristics for all three methods, they deduced the
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dynamical similarity index achieves sensitivity between 21 and 42%. This method was the most sensitive one among these three methods. The drops of the effective correlation dimension were between 13 and 30%, which was the least sensitive methods, and finally but yet importantly method, increments of the accumulated energy lie between 18 and 31% [3]. Entropy, a measure of irregularity or uncertainty, was initially introduced by Shannon (1948) [18]. The famous Shannon entropy formula () is calculated as follows: = log (1)

where pk is the probabilities of a datum in bin k. It can be calculative from this equation that the entropy is high for a broad uniform probability distribution and low for a narrow peaked distribution [18]. This method also detects changes when an episodic behaviour happened while it cannot be noticeable in peak incidences or amplitudes [19]. Approximate Entropy (ApEn) was introduced by Pincus at 1991 [19]. This is a nonlinear method for analysing the irregularity in time series signals [19]. The more irregular the signal is, the larger the ApEn values are, and vice versa [18]. This method can be applied to relatively short, noisy data sets [19]. One of the most important aspects of applying ApEn is it can discriminate both general classes of correlated stochastic processes and noisy deterministic systems [19]. ApEn can be considered as a member of statistics family which emerges to provide a finite sequence, statistically valid formula on the road to discern data sets. The ApEn measures the regularity and estimates both dominant and subordinated patterns in data [19], [20]. Preliminary evidence has shown its usefulness in different EEG studies [20]. In 2001, Christoph Bandt and Bernd Pompe introduce a new method which was permutation entropy [21]. Calculation of time series is simple and fast, in addition the Permutation entropy is a noise alimentation standard [21], [22]. The satisfactory utilization of this method has been reported in the analysis of biomedical signals [23], [24]. The Gabor atom density (GAD) and Autoregressive measure of synchrony (S measure) are two different but complement methods which respectively refer to quantification of the timefrequency components of the EEG and characterize the complexity of the EEG signal and allows for characterization of the degree of synchrony of the EEG
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signal. These methods have been used to recognize if there is an identifiable preictal period or not. By means of these methods, the researchers deduced that both GAD and S measures reveal ictal and prolonged postictal changes; however, there were no significant preictal changes in either complexity or synchrony. Any application of methods to detect preictal changes must be tested on seizures sufficiently separated to avoid residual postictal changes in the potential preictal period [6]. A fuzzy rule-based system is another method for automated epileptic seizure detection which has been employed by A.Aarabi et al. in 2009 [18]. This system based on knowledge extracted from Invasive EEG (IEEG) and then spatio-temporally integrated using the fuzzy rule-based system. This method discriminates the boundaries between interictal and ictal intracranial EEG patterns. Since it is needed to place the intracranial electrodes in to brain or on the cortex, patient should impose on surgical procedure. This issue is the most important disadvantage of this method as it is invasive and always has a risk of infection and cerebral oedema. Beside, the utilization of this system has many advantages that should not be neglected such as: there was only one missed seizure and the system sensitivity was 98.7% [18]. Details of investigation We estimate five steps to meet our objectives. The first step is reviewing the EEG database which is going to be used in the project. We have used the collection of data collected by Ralph G. Andrzejak et al, Department of Epileptolog University of Bonn, Germany [25].

Figure1. Scheme of the locations of surface electrodes according to the international 10-20 system [25].
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They collected five sets (specified A-E) and each set contains 100 single channel Electroencephalography (EEG) segments of 23.6-sec duration. The segments taken from surface EEG recordings of five healthy volunteers using a standardized electrode placement scheme is relative to sets A and B. Volunteers were relaxed in an awake state, while their eyes were open in A and their eyes were closed in B. Sets C, D and E are relevant to EEG archive of pre surgical diagnosis. The archive was EEGs from five patients whom under the complete seizure control after reaction of one of the hippocampal formations, which was therefore correctly diagnosed to be the epileptogenic zone. Set D contains segments recorded within the epileptogenic zone, and Set C includes the segments from hippocampal formation of the opposite hemisphere of the brain. Set E include seizure activity whilst sets C and D consist activity measured continuously during seizure. The sampling rate was 173.61Hz Bandpass filter settings were 0.5340 Hz [25]. The second step is to review published methods for analysis of the EEG in epileptic patients. In the third step we are going to review published non-linear analysis methods for biomedical signal processing. We will write software programs in Matlab to analyse the EEG with non-linear methods in the fourth step. Finally, yet very importantly step, we will validate the implemented methods with EEG signals from the epileptic patients database. Resources needed As the data of this project are already available, the only resource needed will be Matlab software to meet our objective. Since my background is Biomedical Engineering I have been using this software during the Bs degree and I have installed it on my laptop.

Project Plan
Date Literature search Writing the draft of interim Submission the interim Project planning Reviewing the EEG database Reviewing published methods for analysis of the EEG in epileptic patients Reviewing published non-linear analysis methods for biomedical signal processing Write software program in Matlab Extraction non-linear feature and analysis table Estimating the effectiveness of above methods Software testing Writing the draft Correction the draft Submission 15 30 15 Dec 30 Dec 15 Jan 30 Jan 15 Feb 30 15 30 15 29 15 30 15 30 Jun 15 Jul 30 Jul 05 Aug

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References [1] Litt B, Javier E. (2002). Prediction of epileptic seizures. Lancet Neurology ,1,

pp 22-30. [2] Rieke Ch, Mormann F, Andrzejak R, Kreuz T, David P, Elger CH, Lehnertz K. (2003). Discerning nonstationarity from nnonlinearity in sseizure-free and preseizure EEG recordings from epilepsy patients. IEEE transactions on biomedical engineering volume 50, No.5, pp 634-639 [3] Maiwald T,Winterhalder M, Aschenbrenner-Scheibe R, Henning U.Voss, SchulzeBonhage A, Timmer J. (2004). Comparison of three nonlinear seizure prediction methods by means of the seizure prediction characteristic. Physica D 194, pp 357368 [4] Lehnertz EK, Elger CE. (2000). Chaos in the brain? World Scientific, Singapore, in press, pp 1-22. [5] Slutzky MW, Cvitanovic P, Mogul DJ. (2003). Manipulating Epileptiform Bursting in the Rat Hippocampus Using Chaos Control and Adaptive Techniques.IEEE transactions on biomedical engineering, volume .50, No.5, pp.559-570 [6] Jouny CHC, Franaszczuk PJ, Bergey GB. (2005). Signal complexity and synchrony of epileptic seizures: is there an identifiable preictal period?.Clinical

Neurophysiology, 116, pp 552558 [7] Stam CJ(2005). Nonlinear dynamical analysis of EEG and MEG: Review of an emerging field. Clinical Neurophysiology, 116, pp 22662301 [8] Jing H, Takigawa M. (2000) Topographic analysis of dimension estimates

of EEG and filtered rhythms in epileptic patients with complex partial seizures. Biological Cyberneti- cs, 83, pp 391-97. [9] Ubeyli E, Guler I. (2004). Detection of electrocardiographic changes in partial epileptic patients using Lyapunov exponents with multilayer perception neural network s. Engineering Applications of Artificial Intelligence, 17, pp 567-76. [10] Li X, Ouyang G, Yao X. (2004). Dynamical characteristics of pre-epileptic seizures in rats with recurrence quantification analysis. Physics Letters A, 333, pp167-71.

[11] Protopopescu V, Hively L.(2005). Phase space

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nonlinear dynamics: industrial and biomedical applications.Physics, 6, pp649-88. [12] Thakor N, Tong S. (2004). Advances in quantitative EEG analysis methods. Annul Rev. Biomedical engineering, pp. 453-95. [13] Balli T, Palaniappan R. (2009). A combined linear & nonlinear approach for classification of epileptic EEG signals. Proceeding of 4th international conference of the IEEE EMBS, pp 714-17. [14] Mormann F, Kreuz T, Andrzejak RG, David P, Lehnertz K, Elger CHE. (2003). Epileptic seizures are preceded by a decrease in synchronization. Elsevier Science, 53, 173185 [15] Osorio I, Frei M, Lerner D, Wilkinson S. (1998). Real-time automated detection and quantitative analysis of seizures and short-term prediction of clinical onset, Epilepsia, volume 39, No.6, pp 615627 [16] Quyen MLV, Martinerie J, Navarro V, Boon P, DHav M, Adam C, Renault B, Varela F, Baulac M. (2001). Anticipation of epileptic seizures from standard EEG recordings. THE Lancet, volume 357, pp 183-187 [17] Jerger KK, Netoff TI, Francis JT, Sauer T, Pecora L, Weinstein SL, Schiff SJ. (2001). Early Seizure Detection. Journal of Clinical Neurophysiology, volume 18, No. 3, pp259-268 [18] Aarabi A, Fazel-Rezai R, Aghakhani Y. (2009). A fuzzy rule-based system for epileptic seizure detection in intracranial EEG. Clinical Neurophysiology, 120, pp 16481657 [19] Absolo D, Hornero R, Espino P. (2009). Approximate entropy of EEG background activity in Alzheimers disease patients. Intelligent Automation and Soft Computing, Vol. 15, No. 4, pp. 591-603 [20] Absolo D, Escudero J, Hornero R, Gmez C, Espino P. (2008). Approximate entropy and auto mutual information analysis of the electroencephalogram in Alzheimers disease patients. Medical and Biological Engineering and Computing,46, pp10191028 [21] Bandt C, Pompe B. (2002). Permutation entropy -a natural complexity measure for time series. Phys. Rev. Lett. 88(17), PP 174102
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[22] Cao Y, Tung W, Gao J, Protopopescu V, Hively M. (2004). Detecting dynamical chan-ges in time series using the permutation entropy. Phys. Rev. E, 70, PP 046217. [23] Frank B, Pompe B, Schneider U, Hoyer D. (2006). Permutation entropy

improves fatal behavioural state classification based on heart rate analysis from bio magnetic recordings in near term foetuses. Medical and Biological Engineering and Computing, 44, pp 179-87. [24] Olofsen E, Sleigh J, Dahan A. (2008) Permutation entropy of the electroencephalogram: a measure of anaesthetic drug effect. British Journal of Anaesthesia,101,pp 810-21. [25] Andrzejak RG, Lehnertz K, Mormann F, Rieke Ch, David P, Elger ChE. (2001). Indications of nonlinear deterministic and finite-dimensional structures in time series of brain electrical activity: Dependence on recording region and brain state. Journal of the American Physical Society, volume 64, pp 061907-1-8.

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